Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The function of BAD, a proapoptotic member of the Bcl-2 family, is regulated primarily by rapid changes in phosphorylation that modulate its protein-protein interactions and subcellular localization. We show here that, during interleukin-3 (IL-3) deprivation-induced apoptosis of 32Dcl3 murine myeloid precursor cells, BAD is cleaved by a caspase(s) at its N terminus to generate a 15-kDa truncated protein. The 15-kDa truncated BAD is a more potent inducer of apoptosis than the wild-type protein, whereas a mutant BAD resistant to caspase 3 cleavage is a weak apoptosis inducer. Truncated BAD is detectable only in the mitochondrial fraction, interacts with BCL-X(L) at least as effectively as the wild-type protein, and is more potent than wild-type BAD in inducing cytochrome c release. Human BAD, which is 43 amino acids shorter than its mouse counterpart, is also cleaved by a caspase(s) upon exposure of Jurkat T cells to anti-FAS antibody, tumor necrosis factor alpha (TNF-alpha), or TRAIL. Moreover, a truncated form of human BAD lacking the N-terminal 28 amino acids is more potent than wild-type BAD in inducing apoptosis. The generation of truncated BAD was blocked by Bcl-2 in IL-3-deprived 32Dcl3 cells but not in Jurkat T cells exposed to anti-FAS antibody, TNF-alpha, or TRAIL. Together, these findings point to a novel and important role for BAD in maintaining the apoptotic phenotype in response to various apoptosis inducers.
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PMID:Caspase cleavage enhances the apoptosis-inducing effects of BAD. 1128 8

The treatment of sepsis and septic shock remains a clinical conundrum, and recent prospective trials with biological response modifiers aimed at the inflammatory response have shown only modest clinical benefit. Recently, interest has shifted toward therapies aimed at reversing the accompanying periods of immune suppression. Studies in experimental animals and critically ill patients have demonstrated that increased apoptosis of lymphoid organs and some parenchymal tissues contributes to this immune suppression, anergy, and organ system dysfunction. During sepsis syndromes, lymphocyte apoptosis can be triggered by the absence of IL-2 or by the release of glucocorticoids, granzymes, or the so-called 'death' cytokines: tumor necrosis factor alpha or Fas ligand. Apoptosis proceeds via auto-activation of cytosolic and/or mitochondrial caspases, which can be influenced by the pro- and anti-apoptotic members of the Bcl-2 family. In experimental animals, not only can treatment with inhibitors of apoptosis prevent lymphoid cell apoptosis; it may also improve outcome. Although clinical trials with anti-apoptotic agents remain distant due in large part to technical difficulties associated with their administration and tissue targeting, inhibition of lymphocyte apoptosis represents an attractive therapeutic target for the septic patient.
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PMID:Apoptosis in sepsis: a new target for therapeutic exploration. 1129 47

Treatment of patients with non-Hodgkin's lymphoma (NHL) is frequently hampered by development of chemoresistance. Rituximab is a chimeric mouse antihuman CD20 antibody that offers an alternative; however, its mechanism of action is not clearly understood. Treatment of lymphoma cell lines with Rituximab sensitizes the cells to the cytotoxic and apoptotic effects of therapeutic drugs, e.g., cisplatin, fludarabine, vinblastine, and Adriamycin. This study investigated the mechanism(s) involved in the reversal of drug resistance by Rituximab therapy. NHL cells synthesize and secrete antiapoptotic cytokines implicated in drug resistance, including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha. We hypothesized, therefore, that sensitization by Rituximab may be due in part to modification of cytokine production. In this study, examination of cytokine secretion by NHL 2F7 tumor cells revealed down-regulation of IL-10 by Rituximab treatment. Moreover, cytotoxicity assays using exogenous IL-10 and IL-10-neutralizing antibodies demonstrated that IL-10 serves as an antiapoptotic/protective factor in these tumor cells against cytotoxic drugs. Furthermore, expression in 2F7 cells of the protective factor, Bcl-2, was shown to be dependent on IL-10 levels and down-regulated by Rituximab. Other gene products such as Bax, Bcl-x, Bad, p53, c-myc, and latent membrane protein-1 (LMP) were not affected by Rituximab treatment. Drug sensitization, as well as down-regulation of both IL-10 and Bcl-2, was corroborated in experiments using the NHL cell line 10C9. The Ramos and Daudi NHL cell lines were not sensitizable, nor did their Bcl-2 or IL-10 levels change. These studies demonstrate that one mechanism by which Rituximab sensitizes NHL to chemotherapeutic drugs is mediated through down-regulation of antiapoptotic IL-10 autocrine/paracrine loops and Bcl-2. The clinical relevance of these findings is discussed.
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PMID:Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. 1129 68

Elevation of serum interleukin-6 (IL-6) levels is always associated with alcoholic liver disease (ALD), but the significance of such elevation is not clear. Here we show that chronic ethanol consumption induces significant apoptosis in the liver of IL-6 (-/-) mice but not IL-6 (+/+) mice. IL-6 (-/-) hepatocytes are more susceptible to ethanol- and tumor necrosis factor alpha- (TNFalpha-) induced apoptotic killing, which can be corrected by IL-6. Expression of both anti-apoptotic (such as Bcl-2 and Bcl-x(L)) and proapoptotic (such as Bax) proteins is markedly elevated in the liver of human ALD and chronically ethanol-fed IL-6 (+/+) mice. On the contrary, induction of Bcl-2 and Bcl-x(L) is not observed in the liver of chronically ethanol-fed IL-6 (-/-) mice, whereas expression of Bax protein remains elevated. Injection of IL-6 markedly induces expression of Bcl-2 and Bcl-x(L) but not Bax in the liver. Finally, high concentrations of ethanol inhibit IL-6-activated anti-apoptotic signal, but increasing the concentrations of IL-6 is able to overcome such inhibitory effect. These findings suggest that elevated serum IL-6 levels in ALD may overcome the inhibitory effect of ethanol on IL-6-mediated anti-apoptotic signals and prevent alcohol-induced hepatic apoptosis by induction of Bcl-2 and Bcl-x(L).
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PMID:Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-x(L) proteins. 1179 Nov 74

Cytokines produced by immune system cells infiltrating pancreatic islets are candidate mediators of islet beta-cell destruction in autoimmune insulin-dependent diabetes mellitus. After 72 h exposure of human pancreatic islets to a cytotoxic cytokine combination of interleukin 1 beta (50 U/ml), tumor necrosis factor alpha (1,000 U/ml), and interferon gamma (1,000 U/ml), an increase of cell death vs. control islets was demonstrated by TUNEL and cell death detection ELISA method. Islet death was associated with apoptosis and mitochondrial swelling as evidenced by electron microscopy. This effect was correlated with a marked decrease of Bcl-2 mRNA expression (without any major change of Bax mRNA) and a marked increase of inducible nitric oxide synthase mRNA. Since peripheral benzodiazepine receptors constitute the aspecific mitochondrial permeability transition pore, and that it has been suggested to be involved in cytokine-induced cell death, we evaluated the effects of the cytotoxic cytokines on PBR density and mRNA expression. We demonstrated that cytokine treatment of human islets induced an increase of maximum density of (3)H1-(2-chlorophenyl-N-methyl-1-methylpropyl)-3- isoquinolinecarboxamide binding sites, (5,110+/-193 vs. 3,421+/-336 fmol/mg proteins, P<0.05) with no significant change in the affinity constant value (9.45+/-0.869 vs. 8.7+/-1.159 nM). Moreover, an increase of the expression of peripheral benzodiazepine receptor mRNA was observed, suggesting an increased transcription from the coding gene. These results suggest a possible role of peripheral benzodiazepine receptors in the organism response to tissue damage associated with inflammatory mediator production.
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PMID:Upregulation of mitochondrial peripheral benzodiazepine receptor expression by cytokine-induced damage of human pancreatic islets. 1181 68

Fumonisin B1 (FB1) is a naturally occurring mycotoxin produced primarily by Fusarium verticillioides and related fungi, common contaminants of corn throughout the world. FB1 is a carcinogen and causative agent of several lethal animal diseases, including equine leukoencephalomalacia and porcine pulmonary edema. Liver is the primary target organ in mice. In vivo and vitro, cells exposed to FB1 undergo a mixture of necrotic and apoptotic cell death. Our previous studies showed gender differences in hepatotoxicity caused after 5 day FB1 treatment. Gene alterations in cytokine network and apoptosis signaling molecules were also observed after an acute single dose of FB1. To further investigate the gene alterations after a subchronic FB1 exposure and its correlation to observed gender differences, male and female BALB/c mice (five per group) were injected subcutaneously with either saline or 2.25 mg/kg per day of FB1 for 5 days. FB1 caused increased expression of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-10, IL-12 p40, IL-18 and interferon gamma (IFNgamma) in male liver, with a similar increase in females except for IL-1beta and IL-18. Control females showed higher basal levels of IL-1alpha, IL-1Ra, IL-10, IL-12 p40 and IFNgamma compared with males. Expression of TNF receptor 55 and TNF receptor associated death domain (TRADD) was increased, with no changes in Fas signaling molecules, Fas, Fas ligand (FasL), Fas associated death domain (FADD) and Fas-associated protein factor (FAF). Expression of oncogenic transcription factors, c-Myc, B-Myc, Max and Mad, and apoptotic genes, namely Bcl-2, Bax and Bad, was increased after FB1 treatment. FB1 caused an activation of cytokine network in liver, particularly the TNFalpha signaling pathway, suggesting its involvement in hepatotoxic mechanisms. Induction of IL-1Ra and oncogenes is a likely mechanism for the cancer promoting properties of FB1, through a mechanism involving apoptotic necrosis, oncotic necrosis and consequent regeneration.
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PMID:Modulation of selected cell signaling genes in mouse liver by fumonisin B1. 1187 19

Exposure of tumor cells to cytotoxic agents simultaneously activates a variety of intracellular signaling pathways. Some of these pathways involve enzymes from the protein kinase C (PKC) family of serine/threonine kinases. This family includes isoenzymes that negatively influence cell death, whereas other demonstrate an opposite effect. The present study analyzes the role of the zeta atypical PKC isoform in tumor cell response to cytotoxic agents. Using a histone H1 phosphorylation assay, we showed that both tumor necrosis factor alpha and etoposide activate PKCzeta in U937 human leukemic cells. Stable transfection of a kinase-dead, dominant-negative PKCzeta mutant in U937 cells decreases Bcl-2 expression while increasing the expression of Bax and several procaspases. This transfection also prevents etoposide-induced nuclear factor-kappaB nuclear translocation and accumulation of X-linked inhibitor of apoptosis protein. PKCzeta inhibition accelerates the occurrence of apoptosis in leukemic cells exposed to etoposide and tumor necrosis factor alpha. This sensitization was confirmed in vitro by use of a clonogenic assay. In addition, PKCzeta inhibition sensitized tumor cells grown in nude mice to etoposide. These results indicate that PKCzeta isoform is a protective signals that is activated in tumor cells exposed to a cytotoxic agent. This inducible resistance factor thus appears an attractive target for chemosensitization of tumor cells.
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PMID:Atypical protein kinase C zeta as a target for chemosensitization of tumor cells. 1191 60

The mouse mutant "motoneuron disease 2" (MND2, mnd2 on Chr 6) was originally characterized as a spinal muscular atrophy (SMA) because degenerating motoneurons were observed in late stages of the disease. MND2 mutants exhibit a progressive phenotype with neurological symptoms that begin at postnatal day (dP) 20 and include involuntary movements, abnormal postures, akinesis, and death between dP 30 and 40. Unexpectedly, there was no induction of acetylcholine receptor alpha subunit mRNA in skeletal muscle of MND2 mice, an indicator of muscle denervation due to motoneuron loss. Rather, we found a massive loss of striatal neurons beginning at dP 25. Histochemical and ultrastructural analysis revealed nuclear pyknosis, chromatin condensation, and organelle disintegration, combined features of apoptosis and necrosis, characteristic for excitotoxic cell death. Striatal neurodegeneration was accompanied by a pronounced astrogliosis and activation of microglia with macrophage morphology. Motor abnormalities and neuronal loss in MND2 mice were not prevented by neuronal overexpression of a Bcl-2 transgene. Transcripts of several cytokines, including Interleukin-1beta and tumor necrosis factor alpha, were upregulated in the CNS, as well as in lung and spleen, indicating that the mnd2 mutation causes additional pathological effects outside the CNS. Since a 50% reduction in the number of striatal neurons is sufficient to account for the neurological phenotype of MND2 mice, MND2 may be classified as striatal atrophy rather than a primary motor neuron disease. Thus, MND2 mutant mice may provide useful insights into molecular events underlying striatal cell death.
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PMID:Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2. 1200 62

The aim of this study was to examine the effect of two of the most commonly used viral vectors, that is, retrovirus and adenovirus, on the antigen presentation of dendritic cells (DCs). DCs were generated from CD34(+) hematopoietic precursors and CD14(+) monocytes of the same prostate cancer patients. Adenoviral transduction of monocyte-derived DCs (MO-DCs) resulted in upregulation of CD80, CD86, and CD83 expression. Adenovirus-transduced MO-DCs were also more potent stimulators of allogeneic lymphocytes, produced increased amounts of the cytokines tumor necrosis factor alpha and interleukin 12 p70, and exhibited increased expression of NF-kappaB and antiapoptotic molecules Bcl-X(L) and Bcl-2. Enhanced expression of the antiapoptotic molecules correlated with increased resistance of adenovirus-transduced MO-DCs to spontaneous as well as Fas-mediated cell death. In contrast to the adenoviral construct, no significant transduction of MO-DCs with the retrovirus could be obtained. Transduction of CD34(+) cell-derived DCs with the retrovirus or the adenovirus did not significantly alter expression of the costimulatory molecules or cytokines studied. At lower stimulation ratios, CD34(+) cell-derived DCs transduced with retrovirus were less potent in their ability to stimulate allogeneic lymphocytes in comparison with nontransduced DCs. Our results indicate that adenoviral vectors may be more suitable for gene delivery to DCs for immunotherapy.
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PMID:Recombinant adenovirus vector activates and protects human monocyte-derived dendritic cells from apoptosis. 1222 9

The release of cytochrome c from the intermembrane space of mitochondria into the cytosol is one of the critical events in apoptotic cell death. In the present study, it is shown that release of cytochrome c and apoptosis induced by tumor necrosis factor alpha (TNF) in HeLa cells can be inhibited by (i) overexpression of an oncoprotein Bcl-2, (ii) Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore (PTP) or (iii) oligomycin, an inhibitor of H+- ATP-synthase. Staurosporine-induced apoptosis is sensitive to Bcl-2 but insensitive to Cyclosporin A and oligomycin. The effect of oligomycin is not due to changes in mitochondrial membrane potential or to inhibition of ATP synthesis/hydrolysis since (a) uncouplers (CCCP, DNP) which discharge the membrane potential fail to abolish the protective action of oligomycin and (b) aurovertin B (another inhibitor of H+-ATP-synthase, affecting its F1 component) do not affect apoptosis. A role of oligomycin-sensitive F0 component of H+-ATP-synthase in the TNF-induced PTP opening and apoptosis is suggested.
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PMID:Oligomycin, inhibitor of the F0 part of H+-ATP-synthase, suppresses the TNF-induced apoptosis. 1244 50


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